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Fulvestrant ('Faslodex') is a new estrogen receptor (ER) antagonist that has no agonist effects. It binds, blocks and accelerates degradation of the ER, leading to a complete abrogation of estrogen-sensitive gene transcription. In postmenopausal women with advanced breast cancer progressing on prior endocrine therapy, fulvestrant is at least as effective as the third-generation aromatase inhibitor (AI) anastrozole. In this single-center experience, 42 postmenopausal patients with metastatic breast cancer who had been heavily pretreated with prior endocrine therapy and chemotherapy were treated with fulvestrant. Prior endocrine therapies included selective ER modulators (including tamoxifen and toremifene), AIs, megestrol acetate, and high-dose estrogens. In total, eight patients (19%) achieved stable disease (SD) for > or =24 weeks, including two patients with SD for 2 years and one with SD for 14 months. Fulvestrant was well tolerated with the majority of adverse events related to the site of metastatic disease. These data demonstrate that fulvestrant is a well tolerated and effective endocrine therapy for postmenopausal women with metastatic breast cancer who have been heavily pretreated with prior therapies. The novel mechanism of action of fulvestrant reduces the likelihood of cross-resistance with other endocrine therapies and therefore this agent may be active in patients who have proved to be resistant to treatments such as tamoxifen or AIs. The use of fulvestrant earlier in the sequence of endocrine treatments may achieve better responses than observed in this heavily pretreated patient population.

Background: The risk of invasive breast cancer associated with benign breast disease (BBD) other than atypical hyperplasia and in situ breast cancer, especially with nonproliferative diagnosis, has not been explored extensively. This report evaluates the risk of breast cancer associated with this lower-category BBD (LC-BBD)., Methods: 11 307 women without prior history of atypical hyperplasia or in situ breast cancer at randomization (1992-1997) were identified from the cohort of the National Surgical Adjuvant Breast and Bowel Project's Breast Cancer Prevention Trial. Pathologic findings from breast biopsy reports through August 2002 were reviewed, and Cox proportional hazards models were used to determine the relative risks (RRs) of breast cancer with 95% confidence intervals (CIs). The relative risks of breast cancer for LC-BBD were adjusted for treatment and for breast cancer risk as determined by the modified Gail model., Results: Of the 11 307 women, 1376 had LC-BBD, of whom 47 developed breast cancer, and of the 9931 women without LC-BBD, 291 developed breast cancer. The RR of breast cancer for women with LC-BBD relative to women without LC-BBD was 1.60 (95% CI = 1.17 to 2.19). Among women 50 years of age and older, the RR of breast cancer for those with LC-BBD was 1.95 (95% CI = 1.29 to 2.93). After adjustment for treatment and breast cancer risk, the RR of breast cancer for women with LC-BBD was 1.41 (95% CI = 1.03 to 1.94)., Conclusions: Women with LC-BBD had a statistically significant increased risk of breast cancer. The elevation of breast cancer risk was especially evident in women 50 years of age and older. Furthermore, this risk was independent of that associated with key epidemiologic breast cancer risk factors.

Background: In 1998 the National Surgical Adjuvant Breast and Bowel Project (NSABP) demonstrated that tamoxifen treatment reduced the incidence of both invasive and noninvasive breast cancer in women at high risk for the disease. We examined the effect of tamoxifen treatment on the incidence of benign breast disease and the number of breast biopsies in the same group of women., Methods: We examined the medical records of 13 203 women with follow-up who participated in the NSABP Breast Cancer Prevention Trial. Included in this analysis were women who had undergone a breast biopsy and who had histologic diagnoses of adenosis, cyst, duct ectasia, fibrocystic disease, fibroadenoma, fibrosis, hyperplasia, or metaplasia. The relative risk (RR) for each histologic diagnosis was estimated for women who received tamoxifen and for women who received placebo. We also tallied the number of biopsies that women in the placebo and tamoxifen groups underwent., Results: Overall, tamoxifen treatment reduced the risk of benign breast disease by 28% (RR = 0.72, 95% confidence interval [CI] = 0.65 to 0.79). Tamoxifen therapy resulted in statistically significant reductions in the risk of adenosis (RR = 0.59, 95% CI = 0.47 to 0.73), cyst (RR = 0.66, 95% CI = 0.58 to 0.75), duct ectasia (RR = 0.72, 95% CI = 0.53 to 0.97), fibrocystic disease (RR = 0.67, 95% CI = 0.58 to 0.77), hyperplasia (RR = 0.60, 95% CI = 0.50 to 0.71), and metaplasia (RR = 0.51, 95% CI = 0.41 to 0.62). Tamoxifen therapy also reduced the risk for fibroadenoma (RR = 0.77, 95% CI = 0.56 to 1.04) and fibrosis (RR = 0.86, 95% CI = 0.72 to 1.03). Compared with the placebo group, the tamoxifen group had 29% (95% CI = 23% to 34%) fewer biopsies (1048 versus 1469) and 19% fewer women who underwent a biopsy (811 versus 1019). This resulted in a 29% reduction in the risk of biopsy in women treated with tamoxifen (RR = 0.71, 95% CI = 0.66 to 0.77). This risk reduction occurred predominantly in women younger than 50 years., Conclusion: Women in this study who received tamoxifen, especially younger women (i.e., <50 years), had a reduced incidence of clinically detected benign breast disease and underwent fewer breast biopsies.

Trastuzumab (Herceptin) provides clinical benefits for patients diagnosed with advanced breast cancers that have overexpressed the HER2 protein or have amplified the HER2 gene. The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-31 is designed to test the advantage of adding Herceptin to the adjuvant chemotherapeutic regimen of doxorubicin and cyclophosphamide followed by paclitaxel (Taxol) in the treatment of stage II breast cancer with HER2 overexpression or gene amplification. Eligibility is based on HER2 assay results submitted by the accruing institutions. We conducted a central review of the first 104 cases entered in this trial on the basis of immunohistochemistry (IHC) results. We found that 18% of the community-based assays, which were used to establish the eligibility of patients to participate in the B-31 study, could not be confirmed by HercepTest IHC or fluorescence in situ hybridization (FISH) by a central testing facility. This report provides a snapshot of the quality of HER2 assays performed in laboratories nationwide.

HER2 overexpression/amplification, which is an early event in breast cancer development, is associated with a poor prognosis and may predict response to therapy. Herceptin, an anti-HER2 monoclonal antibody, has shown significant efficacy in the treatment of HER2-positive metastatic breast cancer and appears to provide greater benefit the earlier the drug is given. Moreover, Herceptin also demonstrates a favorable safety profile and is associated with quality-of-life benefits. Taken together, these factors provide the rationale for moving this drug into the adjuvant setting, and four large-scale trials that will involve a total of more than 12,000 women with HER2-positive primary breast cancer have been undertaken to address this issue. In the United States, NSABP trial B31 and the Intergroup N9831 trial will investigate Herceptin in combination with the standard US regimen of anthracycline/cyclophosphamide followed by paclitaxel. Trial BCIRG 006, which is being conducted globally, will examine Herceptin in combination with platinum salts/docetaxel. The HERA Trial, involving countries outside the US, will examine q3-weekly Herceptin monotherapy given for 1 and 2 years after the completion of adjuvant chemo-/radiation therapy. The breadth of the ongoing Herceptin adjuvant trials will potentially allow the optimal treatment approach to be identified., (Copyright 2002 S. Karger AG, Basel)

Cancer prevention is a relatively young concept. Perhaps the greatest strides in cancer research that have been made in the prevention arena have been in breast cancer. In this article we examine the meaning of "prevention" and discuss several of the trials under way or completed, including the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial. Semin Oncol 28:253-259., (Copyright 2001 by W.B. Saunders Company.)

Background: This report updated previous findings, at the 15-year mark, of the National Surgical Breast and Bowel Project (NSAPB) Protocol B-06 with respect to the treatment of invasive breast carcinoma and the effects of pathologic features and the effects of some clinical features on its natural history., Methods: Thirty-one pathologic and 6 clinical features that were observed in a pathologic subset of 1039 evaluable patients were assessed as to their value in predicting survival, in predicting ipsilateral breast tumor recurrence (IBTR), and in predicting the necessity for local breast irradiation after lumpectomy. The patients had been randomly assigned to treatment by lumpectomy without local irradiation or to treatment by lumpectomy with local irradiation of the breast. A traditional and another statistical method were used for this purpose., Results: Multivariate analyses revealed that the presence of IBTR, race, histologic tumor type, nodal status, nuclear grade, and blood vessel invasion affected survival independently. Treatment, patient age, nuclear grade, presence of intraductal carcinoma, and a lymphocytic tumor infiltrate were features that predicted IBTR by multivariate analyses. Irradiation reduced IBTR from 36% to 12% in the analyzed cohort. A test of interaction failed to reveal any pathologic or clinical feature that might have allowed for the omission of local irradiation of the breast after lumpectomy., Conclusions: In addition to the influence of pathologic and clinical features on patient survival and IBTR, the site, histopathologic features, and time of occurrence of the latter allowed for insights into some important biologic considerations concerning invasive breast carcinoma., (Copyright 2001 American Cancer Society.)

Purpose: Uncertainty about the relative worth of doxorubicin/cyclophosphamide (AC) and cyclophosphamide/methotrexate/fluorouracil (CMF), as well as doubt about the propriety of giving tamoxifen (TAM) with chemotherapy to patients with estrogen receptor-negative tumors and negative axillary nodes, prompted the National Surgical Adjuvant Breast and Bowel Project to initiate the B-23 study., Patients and Methods: Patients (n = 2,008) were randomly assigned to CMF plus placebo, CMF plus TAM, AC plus placebo, or AC plus TAM. Six cycles of CMF were given for 6 months; four cycles of AC were administered for 63 days. TAM was given daily for 5 years. Relapse-free survival (RFS), event-free survival (EFS), and survival (S) were determined by using life-table estimates. Tests for heterogeneity of outcome used log-rank statistics and Cox proportional hazards models to detect differences across all groups and according to chemotherapy and hormonal therapy status., Results: No significant difference in RFS, EFS, or S was observed among the four groups through 5 years (P =.96,.8, and.8, respectively), for those aged < or = 49 years (P =.97,.5, and.9, respectively), or for those aged > or = 50 years (P =.7,.6, and.6, respectively). A comparison between all CMF- and all AC-treated patients demonstrated no significant differences in RFS (87% at 5 years in both groups, P =.9), EFS (83% and 82%, P =.6), or S (89% and 90%, P =.4). There were no significant differences in RFS, EFS, or S between CMF and AC in patients aged < or = 49 or > or = 50 years. No significant difference in any outcome was observed when chemotherapy-treated patients who received placebo were compared with those given TAM. RFS in both groups was 87% (P =.6), 87% in patients aged < or = 49 (P =.9), and 88% and 87%, respectively (P =.4), in those aged > or = 50 years., Conclusion: There was no significant difference in the outcome of patients who received AC or CMF. TAM with either regimen resulted in no significant advantage over that achieved from chemotherapy alone.

Background: Uncertainty about prognosis and treatment of axillary lymph node-negative patients with estrogen receptor (ER)-negative or ER-positive invasive breast tumors of 1 cm or less prompted the analysis of data from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials., Methods: Two hundred thirty-five patients with ER-negative tumors and 1024 patients with ER-positive tumors were identified in these trials. Patients with ER-negative tumors received surgery alone or surgery and chemotherapy. Patients with ER-positive tumors received surgery alone; surgery and tamoxifen; or surgery, tamoxifen, and chemotherapy. End points were relapse-free survival (RFS), event-free survival, and overall survival. A result was considered to be statistically significant with a P value of.05 or less; all statistical tests were two-sided., Results: The 8-year RFS of women with ER-negative tumors who received surgery alone or with chemotherapy was 81% and 90%, respectively (P = .06). Survival was similar in both groups (93% and 91%; P = .65). The 8-year RFS of women with ER-positive tumors was 86% after surgery alone, 93% when tamoxifen was added (P = .01), and 95% after the addition of tamoxifen and chemotherapy (P = .07 compared with tamoxifen). Survival in the three groups was 90%, 92% (P = .41), and 97%, respectively. The difference between the latter two groups was significant (P = .01). Regardless of ER status or treatment, overall mortality was 8%; one half of the deaths were related to breast cancer. Several covariates affected the risk of recurrence in ER-negative and ER-positive patients. Risk was greater in women with tumors of 1 cm than in those with tumors of less than 1 cm, in women aged 49 years or younger than in those aged 50 years or older, and in women with infiltrating ductal or lobular carcinoma than in those with other histologic tumor types., Conclusions: Chemotherapy and/or tamoxifen should be considered for the treatment of women with ER-negative or ER-positive tumors of 1 cm or less and negative axillary lymph nodes.

Background: Recent retrospective analyses have suggested that breast cancer patients whose tumors overexpress HER2 derive preferential benefit from treatment with anthracyclines such as doxorubicin. This has led some clinicians to propose that HER2 should be used as a predictive marker in choosing between anthracycline-based regimens and combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). We evaluated this recommendation in a retrospective study of National Surgical Adjuvant Breast and Bowel Project Protocol B-15, in which patients received a combination of doxorubicin and cyclophosphamide (AC), CMF, or AC followed by CMF. We hypothesized that AC would be superior to CMF only in the HER2-positive patients., Methods: Immunohistochemical detection of HER2 was performed on tumor sections from 2034 of 2295 eligible patients. We used statistical analysis to evaluate the interaction between the efficacy of the assigned treatments and HER2 overexpression. All statistical tests were two-sided., Results: Tumor sections from 599 patients (29%) stained positive for HER2. AC was superior to CMF in HER2-positive patients only, although differences in outcomes did not reach statistical significance. In the HER2-positive cohort, relative risks of failure (i.e., after AC treatment as compared with CMF treatment) were 0.84 for disease-free survival (DFS) (95% confidence interval [CI] = 0.65--1.07; P =.15), 0.82 for survival (95% CI = 0.63--1.06; P =.14), and 0.80 for recurrence-free survival (RFS) (95% CI = 0.62--1.04; P =.10). Tests for interaction between treatment and HER2 status were suggestive but not statistically significant (P =.19 for DFS, P =.11 for survival, and P =.08 for RFS)., Conclusions: These results, together with overview results indicating minor overall superiority for anthracycline-based regimens relative to CMF, indicate a preference for the AC regimen in patients with HER2-positive tumors. Both AC and CMF regimens may be considered for patients with HER2-negative tumors.

Purpose: In 1989, the National Surgical Adjuvant Breast and Bowel Project initiated the B-22 trial to determine whether intensifying or intensifying and increasing the total dose of cyclophosphamide in a doxorubicin-cyclophosphamide combination would benefit women with primary breast cancer and positive axillary nodes. B-25 was initiated to determine whether further intensifying and increasing the cyclophosphamide dose would yield more favorable results., Patients and Methods: Patients (n = 2,548) were randomly assigned to three groups. The dose and intensity of doxorubicin were similar in all groups. Group 1 received four courses, ie, double the dose and intensity of cyclophosphamide given in the B-22 standard therapy group; group 2 received the same dose of cyclophosphamide as in group 1, administered in two courses (intensified); group 3 received double the dose of cyclophosphamide (intensified and increased) given in group 1. All patients received recombinant human granulocyte colony-stimulating factor. Life-table estimates were used to determine disease-free survival (DFS) and overall survival., Results: No significant difference was observed in DFS (P =.20), distant DFS (P =.31), or survival (P =.76) among the three groups. At 5 years, the DFS in groups 1 and 2 (61% v 64%, respectively; P =. 29) was similar to but slightly lower than that in group 3 (61% v 66%, respectively; P = 08). Survival in group 1 was concordant with that in groups 2 (78% v 77%, respectively; P =.71) and 3 (78% v 79%, respectively; P =.86). Grade 4 toxicity was 20%, 34%, and 49% in groups 1, 2, and 3, respectively. Severe infection and septic episodes increased in group 3. The decrease in the amount and intensity of cyclophosphamide and delays in therapy were greatest in courses 3 and 4 in group 3. The incidence of acute myeloid leukemia increased in all groups., Conclusion: Because intensifying and increasing cyclophosphamide two or four times that given in standard clinical practice did not substantively improve outcome, such therapy should be reserved for the clinical trial setting.

Background: Overexpression of the erbB-2 protein by breast cancer cells has been suggested to be a predictor of response to doxorubicin. A retrospective study was designed to test this hypothesis., Methods: In National Surgical Adjuvant Breast and Bowel Project protocol B-11, patients with axillary lymph node-positive, hormone receptor-negative breast cancer were randomly assigned to receive either L-phenylalanine mustard plus 5-fluorouracil (PF) or a combination of L-phenylalanine mustard, 5-fluorouracil, and doxorubicin (PAF). Tumor cell expression of erbB-2 was determined by immunohistochemistry for 638 of 682 eligible patients. Statistical analyses were performed to test for interaction between treatment and erbB-2 status (positive versus negative) with respect to disease-free survival (DFS), survival, recurrence-free survival (RFS), and distant disease-free survival (DDFS). Reported P values are two-sided., Results: Overexpression of erbB-2 (i.e., positive immunohistochemical staining) was observed in 239 (37.5%) of the 638 tumors studied. Overexpression was associated with tumor size (P=.02), lack of estrogen receptors (P=.008), and the number of positive lymph nodes (P=.0001). After a mean time on study of 13.5 years, the clinical benefit from doxorubicin (PAF versus PF) was statistically significant for patients with erbB-2-positive tumors--DFS: relative risk of failure (RR)=0.60 (95% confidence interval [CI]=0.44-0.83), P=.001; survival: RR=0.66 (95% CI=0.47-0.92), P =.01; RFS: RR=0.58 (95% CI=0.42-0.82), P=.002; DDFS: RR=0.61 (95% CI=0.44-0.85), P=.003. However, it was not significant for patients with erbB-2-negative tumors-DFS: RR=0.96 (95% CI=0.75-1.23), P=.74; survival: RR =0.90 (95% CI=0.69-1.19), P=.47; RFS: RR=0.88 (95% CI=0.67-1.16), P=.37; DDFS: RR=1.03 (95% CI=0.79-1.35), P=.84. Interaction between doxorubicin treatment and erbB-2 overexpression was statistically significant for DFS (P=.02) and DDFS (P=.02) but not for survival (P= .15) or RFS (P=.06)., Conclusions: These data support the hypothesis of a preferential benefit from doxorubicin in patients with erbB-2-positive breast cancer.

Farnesylation is a lipid posttranslational modification required for the biological function of several signaling proteins including the Ras oncoprotein where this modification is required for malignant transformation. Here we report the identification of two distinct farnesyltransferases (FTases) in Burkitt lymphoma Daudi cells. Separation of Daudi cell cytosolic fractions by ion exchange chromatography resulted in two peaks (FTases I and II) that, on gel filtration, show molecular masses of 90 000 and 250 000 Da, respectively. Immunoblotting experiments showed that FTase I is composed of an alpha/beta-heterodimer of about 50 000 Da each. FTase II contained a beta-subunit that is immunologically indistinguishable from the beta-subunit of FTase I and the previously reported human and rat brain FTase but contained an alpha-subunit that reacted poorly with a rat brain anti-alpha-antibody. As in rat brain FTase, Daudi FTases I and II both required magnesium for enzymatic activity. However, their zinc requirements differed. In the absence of Zn2+, FTase I had little activity (10%) whereas FTase II had 30% of its maximum activity (maximum activity obtained in the presence of Zn2+). Furthermore, whereas both FTases I and II were potently inhibited by KB-Ras C-terminal Cys-Val-Ile-Met tetrapeptide mimics, only FTase I but not FTase II required zinc for peptide binding and inhibition.